A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma.

Abstract

RATIONALE:

Microarray data from mouse studies have identified a number of genes to be differentially expressed in allergen-sensitized mice lungs.

OBJECTIVES:

Taking leads from these datasets, we attempted to identify novel genes associated with atopic asthma in humans.

METHODS:

We performed family-based genetic association analysis on selected markers within or in proximity of 21 human homologs of genes short-listed from ovalbumin-sensitized mouse studies in the Gene Expression Omnibus database of the National Center for Biotechnology Information. Family-based and case-control studies were undertaken for fine mapping and functional variation analysis of INPP4A (inositol polyphosphate 4 phosphatase type I). Western blot analysis was performed to analyze INPP4A protein stability from human platelets.

MEASUREMENTS AND MAIN RESULTS:

Our genetic association studies of 21 human genes in 171 trios led to the identification of a biallelic repeat (rs3217304) in INPP4A, associated with atopic asthma (P = 0.009). Further studies using additional three single nucleotide polymorphisms (SNPs), +92031A/T, +92344C/T, and +131237C/T, and two microsatellite markers, D2S2311 and D2S2187, revealed significant genetic associations with loci +92031A/T (P = 0.0012) and +92344C/T (P = 0.004). A nonsynonymous SNP, +110832A/G (Thr/Ala), present within a sequence enriched with proline, glutamic acid, serine, and threonine (PEST), in proximity of these two loci, showed a significant association with atopic asthma (P = 0.0006). The association results were also replicated in an independent cohort of 288 patients and 293 control subjects (P = 0.004). PEST score and Western blot analyses indicated a functional role of this SNP in regulating INPP4A protein stability.

CONCLUSIONS:

In our study, INPP4A was identified as a novel asthma candidate gene, whereby the +110832A/G (Thr/Ala) variant affected its stability and was significantly associated with asthma.

• Authors: Mamta Sharma, Jyotsna Batra, Ulaganathan Mabalirajan, Shilpy Sharma, Rana Nagarkatti, Jyotirmoi Aich, Surendra K Sharma, Pramod V Niphadkar, Balaram Ghosh
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 177 Issue 7 Pg. 712-9 (Apr 01 2008) ISSN: 1535-4970 [Electronic] United States
• PMID: 18187694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL5
• Phosphoric Monoester Hydrolases
• phosphatidylinositol-3,4-bisphosphate 4-phosphatase

Topics

• Adolescent
• Adult
• Asian People (genetics)
• Asthma (epidemiology, genetics)
• Case-Control Studies
• Chemokine CCL5 (blood)
• Family Health
• Female
• Genetic Predisposition to Disease
• Humans
• India (epidemiology)
• Male
• Oligonucleotide Array Sequence Analysis
• Phosphoric Monoester Hydrolases (genetics)
• Polymorphism, Single Nucleotide